Insulin Receptor Substrate-2 Is Not Necessary for Insulin- and Exercise-stimulated Glucose Transport in Skeletal Muscle

• Published in: The Journal of biological chemistry 1999-07, Vol.274 (30), p.20791-20795
• Main Authors: Higaki, Yasuki, Wojtaszewski, Jørgen F.P., Hirshman, Michael F., Withers, Dominic J., Towery, Heather, White, Morris F., Goodyear, Laurie J.
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Glucose - genetics; Glucose - metabolism; Insulin - genetics; Insulin - metabolism; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Male; Mice; Muscle, Skeletal - physiology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Physical Conditioning, Animal; Receptor, Insulin - metabolism; Space life sciences
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.30.20791

Insulin receptor substrate-2-deficient (IRS2−/−) mice develop type 2 diabetes. The purpose of this study was to determine whether there is a defect in basal, insulin-, and exercise-stimulated glucose transport in the skeletal muscle of these animals. IRS2−/− and wild-type (WT) mice (male, 8–10 weeks) exercised on a treadmill for 1 h or remained sedentary. 2-Deoxyglucose (2DG) uptake was measured in isolated soleus muscles incubated in vitro in the presence or absence of insulin. Resting blood glucose concentration in IRS2−/−mice (10.3 mm) was higher than WT animals (4.1 mm), but there was a wide range among the IRS2−/− mice (3–25 mm). Therefore, IRS2−/− mice were divided into two subgroups based on blood glucose concentrations (IRS2−/−L < 7.2 mm, IRS2−/−H > 7.2 mm). Only IRS2−/−H had lower basal, exercise-, and submaximally insulin-stimulated 2DG uptake, while maximal insulin-stimulated 2DG uptake was similar among the three groups. The ED50 for insulin to stimulate 2DG uptake above basal in IRS2−/−H was higher than WT and IRS2−/−L mice, suggesting insulin resistance in the skeletal muscle from the IRS2−/− mice with high blood glucose concentrations. Furthermore, resting blood glucose concentrations from all groups were negatively correlated to submaximally insulin-stimulated 2DG uptake (r2 = 0.33, p < 0.01). Muscle GLUT4 content was significantly lower in IRS2−/−H mice compared with WT and IRS2−/−L mice. These results demonstrate that the IRS2 protein in muscle is not necessary for insulin- or exercise-stimulated glucose transport, suggesting that the onset of diabetes in the IRS2−/− mice is not due to a defect in skeletal muscle glucose transport; hyperglycemia may cause insulin resistance in the muscle of IRS2−/− mice.